Transition-metal-free regioselective C-H halogenation of imidazo[1,2-: A] pyridines: Sodium chlorite/bromite as the halogen source

Article abstract of DOI:10.1039/c7ra12100h

A facile transition-metal-free regioselective halogenation of imidazo[1,2-a]pyridines using sodium chlorite/bromite as the halogen source is presented. The reaction has provided an efficient method for the formation of C-Cl or C-Br bonds to synthesize 3-c

Full text of DOI:10.1039/c7ra12100h

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Transition-metal-free regioselective C–H
halogenation of imidazo[1,2-a]pyridines: sodium
chlorite/bromite as the halogen source†
Cite this: RSC Adv., 2018, 8, 5058
*
*
Junxuan Li, Jiayi Tang, Yuanheng Wu, Qiuxing He and Yue Yu
Received 3rd November 2017
Accepted 23rd January 2018
A facile transition-metal-free regioselective halogenation of imidazo[1,2-a]pyridines using sodium chlorite/
bromite as the halogen source is presented. The reaction has provided an efficient method for the
formation of C–Cl or C–Br bonds to synthesize 3-chloro or 3-bromo-imidazo[1,2-a]pyridines which
were then efficiently transformed into imidazo[1,2-a]pyridine core p-systems by Suzuki–Miyaura reactions.
DOI: 10.1039/c7ra12100h
rsc.li/rsc-advances
Aryl halides as a structural skeleton are present in a large years, several transition-metal-catalyzed halogenation trans-
number of natural products, pharmaceuticals, and biologically formations11,12 have been developed, employing Pd, Rh or Cu as
active compounds.1 Signicant drugs such as Aripiprazole, the catalysts and carboxylic acid, amide, nitrile, or pyridine as
Chlortrimeton, Plavix and Zolo all included the aryl chlorides the directing groups (Scheme 1a). Recently, NH4X, NaX and HX
motif (Scheme 1). Apart from this, aryl bromides have always have been also employed as the halogen sources13 in transition-
been extremely important synthetic intermediates and building metal-free conditions for the halogenation of several arenes and
blocks in organic chemistry2 for the construction of diverse and heteroarenes (Scheme 1b). Nevertheless, directing groups and
highly functionalized compounds. In the past few years, aryl additional oxidants were usually needed in these trans-
halides have been used as substrates to form carbon–carbon formations and the halogen sources were very limited.
and carbon–heteroatom bonds via transition-metal-catalyzed
In order to expand the richness of green synthetic methods,
cross-coupling reactions. There are some classical methods: we tried to hunt for other atom-economical and easy-to-obtain
Heck, Suzuki, Negishi, Stille, Sonogashira, Ullmann, Buchwald– halogen sources. As we know, sodium chlorite or bromite are
Hartwig, Kumada, etc.3–10 Consequently, the development of commodity chemicals that are widely used as main effective
a new route for the construction of these scaffolds is highly components of bleaches or desizing agents.14 On the other
desirable, especially those based on assembling structures hand, imidazo[1,2-a]pyridines represent an important class of
directly from readily available raw materials. In the last few molecules and show unique bioactivities and chemical prop-
erties15 that lead them to broad applications in organic
synthesis and pharmaceutical chemistry.16 Recent signicant
advances17 have been achieved in this eld. We have also
developed novel strategies for the construction of imidazo[1,2-
a]pyridines.18 Herein, our current interest is focused on devel-
oping an efficient transition-metal-free selective halogenation
of imidazo[1,2-a]pyridines without direct group, in which
process sodium chlorite or bromite were used as both halogen
sources and oxidants (Scheme 2c).
Our initial investigation focused on the halogenation of
imidazo[1,2-a]pyridine 1a. The results of the optimized reaction
conditions are summarized in Table 1. The reaction was con-
ducted in the presence of NaClO2 (1 equiv.), AcOH (2 mmol), in
ꢀ
toluene at 60 C for 10 h (Table 1, entry 1). To our delight, the
Scheme 1 Chlorine containing drugs.
desired product 2a was formed in 64% yield. No regioisomeric
products were observed by GC-MS and H NMR spectroscopy.
1
Being delighted by this result, we then carried out the different
optimization experiments to obtain the optimal reaction
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical
University, Zhongshan 528458, P. R. China. E-mail: yuyue@gdpu.edu.cn;
conditions. Various amounts of NaClO2 were next survey for this
heqiuxing@126.com; Fax: +86 760 88207939
transformation (Table 1, entries 2–3). A similar yield was
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra12100h
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indicated that product 2a was not generated in the absence of
NaClO2 (Table 1, entry 16).
With the establishment of the optimal conditions, the scope
of this transition-metal-free chlorination reaction was next
investigated. And the results have been described in Scheme 3.
A variety of 2-unsubstituted imidazo[1,2-a]pyridines were rst
employed under the optimized conditions. Different position
substituted groups on the pyridine ring of imidazo[1,2-a]pyri-
dine, having 6-CH3, 6-Cl, 6-I, 7-CH3, 8-CH3 substitution, were
well-tolerated under the optimized conditions. The results
indicated that selective C-3 chlorination products 2a–2f were
formed in good to excellent yields. This catalytic system was
further found to be successfully applied to catalyze the chlori-
nation of 2-CH3, 2-C(CH3)3, and 2-Ph substituted imidazo[1,2-a]
pyridines, generating the desired products in moderate to good
yields (2g–2p). It was worth noting that when imidazo[1,2-a]
pyridines substituted with sterically hindered 2-C(CH3)3 were
employed as substrates, the transformation worked well and led
to a benecial effect on the reaction outcome.
Scheme 2 Selective halogenation reactions.
Table 1 Optimization of the reaction conditionsa
We next examined the bromination of imidazo[1,2-a]pyri-
dines derivatives in the presence of NaBrO2 and AcOH in DMF
at 60 ꢀC for 10 h. The results were summarized in Scheme 4. As
we expected, the optimal conditions could also be applied to
bromination of imidazo[1,2-a]pyridines and afforded the
brominated products 3a–3f in 70–88% yields. It was found that
the reaction was also with great regioselective in the case of 2-
unsubstituted imidazo[1,2-a]pyridines.
The reactions of 2a or 3d with phenylboronic acid were
conducted in the presence of Pd-catalyst (Scheme 5). The
Suzuki–Miyaura reactions were performed very well, affording
the product 5a or 6a in 74% or 79% yields, respectively.
In order to text whether this method is compatible with other
aromatic species or not, we have tried to use indoles, 1-methyl-
Entry NaClO2 (equiv.) Additive
Solvent Temp (ꢀC) Yieldb (%)
1
2
3
1
2
2
2
2
2
2
2
2
2
2
2
2
2
AcOH
AcOH
AcOH
Toluene 60
Toluene 60
Toluene 60
64
62
43
2
3
4
CF3COOH Toluene 60
40
5
6
7
PivOH
TsOH
—
Toluene 60
Toluene 60
Toluene 60
Dioxane 60
29
31
Trace
69
8
9
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
NMP
60
45
10
11
12
13
14
15
16c
CH3CN 60
37
DMSO
DMF
DCE
DMF
DMF
DMF
60
60
60
40
80
60
63
87
14
74
85
n.r.
a
Reaction conditions: 1a (0.5 mmol), NaClO2 (1–3 mmol), AcOH (2
b
mmol), solvent (2 mL), 40–80 ꢀC for 10 h. Determined by GC
analysis. c Without NaClO2.
obtained aer increasing the amount of NaClO2 to 3 equiv.,
while a decreased yield was observed aer decreasing the
amount from 2 to 1 equiv. Among the set of additives examined,
AcOH gave the desired product 2a in good yield, while CF3-
COOH, PivOH and TsOH were found to be less effective in
affording the corresponding product 2a in 29–40% yield (Table
1, entries 4–6). It was worth noting that if acid was not added,
only trace amount of target product was generated (Table 1,
entry 7). The effect of solvents was further tested. It was found
that DMF was the best choice in comparison to toluene, 1,4-
dioxane, NMP, CH3CN, DMSO and DCE (Table 1, entries 8–13).
We then screened the reaction temperature and found the
ꢀ
ꢀ
reaction performed at 40 C or 80 C gave a lower yield of the
product 2a (Table 1, entries 14–15). The control experiment
Scheme 3 Chlorination of imidazo[1,2-a]pyridines.
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Scheme 7 Control experiments for investigation of the mechanism.
Scheme 4 Bromination of imidazo[1,2-a]pyridines.
Scheme 8 Possible mechanism.
Scheme 5 Suzuki–Miyaura reactions of 2a or 3d with phenylboronic
(TEMPO) or radical inhibitor (BHT) (Scheme 7, eqn (1)) in the
reaction, and only trace amount of product 2a was observed. The
result clearly showed that this reaction had been inhibited and
a radical process was involved for this transformation, which
was consistent with previous reported.17 To further investigated
the chlorine source, NaClO and NaClO3 were employed to react
with imidazo[1,2-a]pyridine 2a under the standard conditions.
The results showed that the chlorination products were obtained
in yields of 47% or 63% respectively, which means chlorine ions
having a charge of 1+ or 5+ can also proceed this transformation,
albeit with low yields (Scheme 7, eqn (2)).
Base on the above results and previous works,19 a possible
mechanism was proposed to account for this transition-metal-
free regioselective halogenation reaction (Scheme 8). Firstly,
oxidation–reduction reaction of sodium chlorite happened in
the presence of AcOH to produce chlorine, NaOAc and H2O.
Subsequently, the chlorine radical was easily formed via
homolysis of chlorine, which then attack the double bond
between C2 and C3 of imidazo[1,2-a]pyridine, resulting in free
radical intermediate I (more stable than II because of the p–p
conjugation). Finally, the free radical intermediate I underwent
an aromatization with chlorine free radical to give the target
product 2a.
acid.
1H-indoles, benzofurans, N,N-dimethylaniline, N-phenyl-
acetamide and 1,3,5-trimethoxybenzene to perform under the
present reaction conditions, while no target products were ob-
tained. We supposed that the specicity of this reported method
is because of the rich electronic ethene-1,2-diamine moiety of
imidazo[1,2-a]pyridine (Scheme 6).
Gaining insight into the mechanism, control experiments
were carried out for this transition-metal-free halogenation
reaction. To prove a radical species involved in transformation,
the reactions were conducted by adding radical-trapping reagent
Conclusions
In conclusion, we have developed an efficient transition-metal-
free regioselective C–H functionalization approach. The
Scheme 6 Applications for other aromatic species.
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reaction provides a new selective route to synthesize 3-Cl or 3-
Br-imidazo[1,2-a]pyridines without directing groups. The use of
cheap sodium chlorite or bromite as both halogenic sources
and oxidants is a major advantage. The 3-Cl or 3-Br-imidazo[1,2-
a]pyridines as the substrates can successful apply to Suzuki–
Miyaura reactions.
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There are no conicts to declare.
Acknowledgements
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